Abstract: Ruthenium–arene complexes bearing N-heterocyclic carbene (NHC) ligands with the generic formula [RuCl2(p-cymene)(NHC)] are efficient catalyst precursors for the cyclopropanation of activated olefins with ethyl diazoacetate, and the cis/trans diastereoselectivity of the reaction markedly depends on the steric bulk of the NHC. The procedure was successfully applied to styrene, α-methylstyrene, and various other styrenic derivatives bearing electron-withdrawing or donating substituents on their aromatic rings. The reaction of unactivated internal or terminal alkenes was more sluggish, and the use of norbornene as a substrate afforded only olefin metathesis. Further investigation of the ring-opening metathesis polymerization of this strained cycloolefin in the presence of trimethylsilyldiazomethane led to high molecular weight polynorbornene whose microstructure was not significantly affected by the choice of the NHC ancillary ligand. [less ▲]

Deprotonation of 1,3-di(2-tolyl)benzimidazolium tetrafluoroborate with a strong base afforded 1,3-di(2-tolyl)benzimidazol-2-ylidene (BTol), which dimerized progressively into the corresponding ... [more ▼]

Deprotonation of 1,3-di(2-tolyl)benzimidazolium tetrafluoroborate with a strong base afforded 1,3-di(2-tolyl)benzimidazol-2-ylidene (BTol), which dimerized progressively into the corresponding dibenzotetraazafulvalene. The complexes [RhCl(COD)(BTol)] (COD is 1,5-cyclooctadiene) and cis-[RhCl(CO)2(BTol)] were synthesized to probe the steric and electronic parameters of BTol. Comparison of the percentage of buried volume (%VBur) and of the Tolman electronic parameter (TEP) of BTol with those determined previously for 1,3-dimesitylbenzimidazol-2-ylidene (BMes) revealed that the two N-heterocyclic carbenes displayed similar electron donicities, yet the 2-tolyl substituents took a slightly greater share of the rhodium coordination sphere than the mesityl groups, due to a more pronounced tilt. The anti,anti conformation adopted by BTol in the molecular structure of [RhCl(COD)(BTol)] ensured nonetheless a remarkably unhindered access to the metal center, as evidenced by steric maps. Second-generation ruthenium-benzylidene and isopropoxybenzylidene complexes featuring the BTol ligand were obtained via phosphine exchange from the first generation Grubbs and Hoveyda-Grubbs catalysts, respectively. The atropisomerism of the 2-tolyl substituents within [RuCl2([double bond, length as m-dash]CHPh)(PCy3)(BTol)] was investigated by using variable temperature NMR spectroscopy, and the molecular structures of all four possible rotamers of [RuCl2([double bond, length as m-dash]CH-o-OiPrC6H4)(BTol)] were determined by X-ray crystallography. Both complexes were highly active at promoting the ring-closing metathesis (RCM) of model [small alpha],[small omega]-dienes. The replacement of BMes with BTol was particularly beneficial to achieve the ring-closure of tetrasubstituted cycloalkenes. More specifically, the stable isopropoxybenzylidene chelate enabled an almost quantitative RCM of two challenging substrates, viz., diethyl 2,2-bis(2-methylallyl)malonate and N,N-bis(2-methylallyl)tosylamide, within a few hours at 60 °C. [less ▲]

N-heterocyclic carbene catalyzed Michael additions have been revisited with 1,3-dialkyl- or 1,3-diarylimidazol(in)ium-2-carboxylates, that is, NHC·CO2 adducts, as the source of the free NHC catalysts in ... [more ▼]

N-heterocyclic carbene catalyzed Michael additions have been revisited with 1,3-dialkyl- or 1,3-diarylimidazol(in)ium-2-carboxylates, that is, NHC·CO2 adducts, as the source of the free NHC catalysts in solution. Using these precatalysts, a number of efficient carba-, sulfa-, and phospha-Michael additions were achieved very conveniently, without the need for an external strong base to generate the NHC by deprotonation of an azolium salt. To further expand the scope of the procedure, some NHC-catalyzed sulfa-Michael/aldol organocascades were also investigated. [less ▲]

Synthesis of biologically active compounds is of paramount importance to the biomedical sciences for the development of novel therapeutic agents. Such substances often feature various types of unique and ... [more ▼]

Synthesis of biologically active compounds is of paramount importance to the biomedical sciences for the development of novel therapeutic agents. Such substances often feature various types of unique and complex structures, which make them challenging targets for synthetic efforts. Their total synthesis offers the chance to implement the use of newly developed, efficient and highly selective synthetic procedures and/or strategies in a complex environment. In this respect, thanks to the development of increasingly efficient molybdenum and ruthenium catalysts, olefin metathesis is now an integral part of modern synthetic methods. This review article will highlight with selected examples from the recent literature assets and limitations of the olefin metathesis reaction in the synthesis of biologically active compounds. [less ▲]

This paper surveys recent advances in valorization of transition-metal-catalyzed enyne metathesis as key events in the total synthesis of naturally occurring compounds of biological and medicinal ... [more ▼]

This paper surveys recent advances in valorization of transition-metal-catalyzed enyne metathesis as key events in the total synthesis of naturally occurring compounds of biological and medicinal importance. Special attention is devoted to methodologies based on dienyne ring-closing metathesis (RCM) applied in tandem and sequential processes, on relay ring-closing metathesis (RRCM), ring-rearrangement metathesis (RRM), enyne cross-metathesis (CM) and enyne skeletal bond reorganization, all proceeding under metalcarbenes (Ru or Mo alkylidenes) or metal-salts (Pd or Pt) catalysis. The high potential of these procedures in constructing versatile scaffolds as essential structural cores of a diversity of bioactive natural products is highlighted. Inventive functionalizations by non-metathesis transformations intervening in the total synthesis of the targeted natural compounds, prior to (Michael addition, Wittig olefination, allylation etc.) or after (Diels-Alder cycloaddion, Heck and Suzuki-Miyaura reactions, Dess-Martin oxidation, dihydroxylation, epoxidation etc.) the pivotal metathesis step have also been included. [less ▲]

Four zwitterions were prepared by treating 1,3-dimesitylimidazolin-2-ylidene (SIMes) or 1,3-dimesitylimidazol-2-ylidene (IMes) with either N-tosyl benzaldimine or diphenylketene. They were isolated in ... [more ▼]

Four zwitterions were prepared by treating 1,3-dimesitylimidazolin-2-ylidene (SIMes) or 1,3-dimesitylimidazol-2-ylidene (IMes) with either N-tosyl benzaldimine or diphenylketene. They were isolated in high yields and characterized by IR and NMR spectroscopy. The molecular structures of three of them were determined by using X-ray crystallography and their thermal stability was monitored by using thermogravimetric analysis. The imidazol(in)ium-2-amides were rather labile white solids that did not show any tendency to tautomerize into the corresponding 1,2,2-triaminoethene derivatives. They displayed a mediocre catalytic activity in the Staudinger reaction of N-tosyl benzaldimine with diphenylketene. In contrast, the imidazol(in)ium-2-enolates were orange-red crystalline materials that remained stable over extended periods of time. Despite their greater stability, these zwitterions turned out to be efficient promoters for the model cycloaddition under scrutiny. As a matter of fact, their catalytic activity matched those recorded with the free carbenes. Altogether, these results provide strong experimental insight into the mechanism of the Staudinger reaction catalyzed by N-heterocyclic carbenes. They also highlight the superior catalytic activity of the imidazole-based carbene IMes compared with its saturated analogue SIMes in the reaction under consideration. [less ▲]

The deprotonation of 1,3-dimesitylbenzimidazolium tetrafluoroborate with a strong base afforded 1,3-dimesitylbenzimidazol-2-ylidene (BMes), which was further reacted in situ with rhodium or ruthenium ... [more ▼]

The deprotonation of 1,3-dimesitylbenzimidazolium tetrafluoroborate with a strong base afforded 1,3-dimesitylbenzimidazol-2-ylidene (BMes), which was further reacted in situ with rhodium or ruthenium complexes to afford three new organometallic products. The compounds [RhCl(COD)(BMes)] (COD is 1,5-cyclooctadiene) and cis-[RhCl(CO)2(BMes)] were used to probe the steric and electronic parameters of BMes. Comparison of the percentage of buried volume (%VBur) and of the Tolman electronic parameter (TEP) of BMes with those determined previously for 1,3-dimesitylimidazol-2-ylidene (IMes) and 1,3-dimesitylimidazolin-2-ylidene (SIMes) revealed that the three N-heterocyclic carbenes (NHCs) had very similar profiles. Nonetheless, changes in the hydrocarbon backbone subtly affected the stereoelectronic properties of these ligands. Accordingly, the corresponding [RuCl2(PCy 3)(NHC)(CHPh)] complexes displayed different catalytic behaviors in the ring-closing metathesis (RCM) of α,ω-dienes. In the benchmark cyclization of diethyl 2,2-diallylmalonate, the new [RuCl2(PCy 3)(BMes)(CHPh)] compound (1d) performed slightly better than the Grubbs second-generation catalyst (1a), which was in turn significantly more active than the related [RuCl2(PCy3)(IMes)(CHPh)] initiator (1b). For the formation of a model trisubstituted cycloolefin, complex 1d ranked in-between catalyst precursors 1a and 1b, whereas in the RCM of tetrasubstituted cycloalkenes it lost its catalytic efficiency much more rapidly. [less ▲]

Preformed or in situ generated monometallic ruthenium-arene complexes with the generic formula RuX2(arene)(L) (L = phosphine or N-heterocyclic carbene) are versatile and efficient catalyst precursors for olefin metathesis and atom transfer radical reactions. Their synthesis is usually accomplished using simple and straightforward experimental procedures starting from the [RuCl2(p-cymene)]2 dimer. This article retraces their evolution over the past 20 years and highlights similarities and differences with the parallel development of well-defined RuX2(CHR)(L1)(L2) ruthenium-alkylidene catalysts. [less ▲]

The oxidation of various N,N′-diarylbenzene-1,2-diamines bearing bulky aromatic substituents with sodium periodate on wet silica gel afforded a series of five new dihydrophenazines instead of the expected ... [more ▼]

The oxidation of various N,N′-diarylbenzene-1,2-diamines bearing bulky aromatic substituents with sodium periodate on wet silica gel afforded a series of five new dihydrophenazines instead of the expected cyclohexadiene-1,2-diimines. The reaction most likely proceeds via a 1,6-electrocyclic path and provides a convenient access to an important class of nitrogen heterocycles. Subsequent treatment of the mesityl derivative with chloromethyl pivalate and silver triflate led to the corresponding benzimidazolium salt. [less ▲]

The catalytic activity of a series of homobimetallic ruthenium complexes of the type [(p-cymene)Ru(μ-Cl)3RuCl(L)(L′)] [L = C2H4 or a vinylidene ligand (=C=CHR); L′ = PPh3, PCy3, or an N-heterocyclic ... [more ▼]

The catalytic activity of a series of homobimetallic ruthenium complexes of the type [(p-cymene)Ru(μ-Cl)3RuCl(L)(L′)] [L = C2H4 or a vinylidene ligand (=C=CHR); L′ = PPh3, PCy3, or an N-heterocyclic carbene ligand] was determined by investigating the atom transfer radical polymerisation of methyl methacrylate. The results clearly demonstrate that the ligands strongly affect the ability of the ruthenium complexes to favour the occurrence of a well-behaved ATRP. [less ▲]

The new homobimetallic ruthenium–vinylidene complex [(p-cymene)Ru(μ-Cl)3RuCl(═C═CHPh)(IMes)] (6) was isolated in high yield upon treatment of [(p-cymene)Ru(μ-Cl)3RuCl(η2-C2H4)(IMes)] (5) with a slight ... [more ▼]

The new homobimetallic ruthenium–vinylidene complex [(p-cymene)Ru(μ-Cl)3RuCl(═C═CHPh)(IMes)] (6) was isolated in high yield upon treatment of [(p-cymene)Ru(μ-Cl)3RuCl(η2-C2H4)(IMes)] (5) with a slight excess of phenylacetylene at −50 °C. Although it was very stable under normal atmosphere in the solid state, this product underwent an oxidative cleavage into the corresponding carbonyl compound [(p-cymene)Ru(μ-Cl)3RuCl(CO)(IMes)] (7) when dissolved in oxygen-containing solvents. Second-generation complexes 6 and 7 were characterized by IR and NMR spectroscopies, and their molecular structures were determined by X-ray diffraction analysis. The catalytic activity of complex 6 was probed in various types of olefin metathesis reactions. Compared to its first-generation analogue [(p-cymene)Ru(μ-Cl)3RuCl(═C═CHPh)(PCy3)], the new ruthenium initiator displayed an enhanced activity. It was also much more selective than ruthenium–ethylene complex 5. Aluminum chloride was a valuable cocatalyst for the ROMP of cyclooctene, whereas phenylacetylene was better suited to achieve the fast and quantitative RCM of α,ω-dienes into the corresponding di- or trisubstituted cycloolefins. The role of the terminal alkyne was rationalized by assuming that it would allow an enyne metathesis to take place, thereby transforming saturated vinylidene precursor 6 into a highly active mono- or bimetallic ruthenium–alkylidene species. [less ▲]

Five imidazol(in)ium-2-thiocarboxylates bearing cyclohexyl, mesityl, or 2,6-diisopropylphenyl substituents on their nitrogen atoms were prepared from the corresponding imidazol(in)ium chlorides or ... [more ▼]

Five imidazol(in)ium-2-thiocarboxylates bearing cyclohexyl, mesityl, or 2,6-diisopropylphenyl substituents on their nitrogen atoms were prepared from the corresponding imidazol(in)ium chlorides or tetrafluoroborates in a one-pot, two-step procedure involving the in situ generation of free N-heterocyclic carbenes (NHCs) with a strong base followed by trapping with carbonyl sulfide. The resulting NHC•COS zwitterions were isolated in high yields and characterized by IR and NMR spectroscopy. The molecular structure of SIMes•COS was determined by X-ray diffraction analysis. Experimental data and DFT calculations indicated that the negative charge on the thiocarboxylate anion is preferentially delocalized on the sulfur atom. Thermogravimetric analysis showed that the NHC•COS zwitterions undergo thermolysis at temperatures ranging between 110 and 180 °C in the solid state. They are also rather labile in solution. Unlike the related NHC•CS2 betaines, which are highly stable, crystalline materials, they displayed the same type of behavior as the analogous carboxylate adducts, which readily lose their CO2 moiety upon heating or dissolution. Thus, imidazol(in)ium-2-thiocarboxylates acted as convenient NHC precursors in two model organocatalytic transformations. Of the five thiocarboxylates examined, ICy•COS was the most efficient at promoting the acylation of benzyl alcohol with vinyl acetate, whereas SIMes•COS afforded the highest activity in benzoin condensation. [less ▲]

The new 2-phenylthiocarbamoyl-1,3-dimesitylimidazolium inner salt (IMes•CSNPh) reacts with [AuCl(L)] in the presence of NH4PF6 to yield [(L)Au(SCNPh•IMes)]+ (L = PMe3, PPh3, PCy3, CNBut). The carbene-containing precursor [(IDip)AuCl] reacts with IMes•CSNPh under the same conditions to afford the complex [(IDip)Au(SCNPh•IMes)] + (IDip = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene). Treatment of the diphosphine complex [(dppm)(AuCl)2] with one equivalent of IMes•CSNPh yields the digold metallacycle, [(dppm)Au 2(SCNPh•IMes)]2+, while reaction of [L 2(AuCl)2] with two equivalents of IMes•CSNPh results in [(L2){Au(SCNPh•IMes)}2]2+ (L2 = dppb, dppf, or dppa; dppb = 1,4-bis(diphenylphosphino)butane, dppf = 1,1'-bis(diphenylphosphino)ferrocene, dppa = 1,4- bis(diphenylphosphino)acetylene). The homoleptic complex [Au(SCNPh•IMes) 2]+ is formed on reaction of [AuCl(tht)] (tht = tetrahydrothiophene) with two equivalents of the imidazolium-2- phenylthiocarbamoyl ligand. This product reacts with AgOTf to yield the mixed metal compound [AuAg(SCNPh•IMes)2]2+. Over time, the unusual trimetallic complex [Au(AgOTf)2(SCNPh•IMes) 2]+ is formed. The sulfur-oxygen mixed-donor ligands IMes•COS and SIMes•COS (SIMes = 1,3-bis(2,4,6-trimethylphenyl) imidazolin-2-ylidene) were used to prepare [(L)Au(SOC•IMes)]+ and [(L)Au(SOC•SIMes)]+ from [(L)AuCl] (L = PPh3, CNtBu). The bimetallic examples [(dppf){Au(SOC•IMes)} 2]2+ and [(dppf){Au(SOC•SIMes)}2] 2+ were synthesized from the reaction of [(dppf)(AuCl)2] with the appropriate ligand. Reaction of [(tht)AuCl] with one equivalent of IMes•COS or SIMes•COS yields [Au(SOC•IMes) 2]+ and [Au(SOC•SIMes)2]+, respectively. The compounds [(Ph3P)Au(SCNPh•IMes)]PF 6, [(Cy3P)Au(SCNPh•IMes)]PF6 and [Au(AgOTf)2(SCNPh•IMes)2]OTf were characterized crystallographically. [less ▲]

Five new complexes with the generic formula [RuCl(2)(p-cymene)(SOC.NHC)] (2-6) were isolated in high yields by reacting the [RuCl(2)(p-cymene)](2) dimer with a range of imidazol(in)ium-2-thiocarboxylate ... [more ▼]

Five new complexes with the generic formula [RuCl(2)(p-cymene)(SOC.NHC)] (2-6) were isolated in high yields by reacting the [RuCl(2)(p-cymene)](2) dimer with a range of imidazol(in)ium-2-thiocarboxylate zwitterions bearing cyclohexyl, 2,4,6-trimethylphenyl (mesityl), or 2,6-diisopropylphenyl groups on their nitrogen atoms in CH(2)Cl(2) at -20 degrees C. All the products were fully characterized by IR and NMR spectroscopy, and the molecular structures of [RuCl(2)(p-cymene)(SOC.IMes)] (3) and [RuCl(2)(p-cymene)(SOC.SIMes)] (5) were determined by X-ray diffraction analysis. Coordination of the NHC.COS ligands took place via the sulfur atom. A remarkable shielding of the methine proton on the p-cymene isopropyl group was observed by (1)H NMR spectroscopy for complexes 3-6. It is most likely caused by the aromatic ring current of a neighboring mesityl or 2,6-diisopropylphenyl substituent. The catalytic activity of compounds 2-6 was probed in the ring-opening metathesis polymerization (ROMP) of cyclooctene, in the atom transfer radical polymerization (ATRP) of methyl methacrylate, and in the synthesis of enol esters from 1-hexyne and 4-acetoxybenzoic acid. In all these reactions, the [RuCl(2)(p-cymene)(SOC.NHC)] complexes displayed performances slightly inferior to those exhibited by [RuCl(2)(p-cymene)(NHC)] species that result from the reaction of [RuCl(2)(p-cymene)](2) with NHC.CO(2) inner salts. However, they were significantly better catalyst precursors than the much more robust chelates of the [RuCl(p-cymene)(S(2)C.NHC)PF(6) type obtained by coordination of NHC.CS(2) betaines to the ruthenium dimer. These results suggest that the Ru-(SOC.NHC) motif undergoes a dethiocarboxylation under the experimental conditions adopted for the catalytic tests and leads to the same elusive Ru-NHC active species as the preformed [RuCl(2)(p-cymene)-(NHC)] family of complexes. [less ▲]

In this Chapter, the catalytic applications of organometallic species -either pre-formed or generated in situ- based on Group 8 transition metals and N-heterocyclic carbene (NHC) ligands are surveyed ... [more ▼]

In this Chapter, the catalytic applications of organometallic species -either pre-formed or generated in situ- based on Group 8 transition metals and N-heterocyclic carbene (NHC) ligands are surveyed. Thus far, only a few reports on the use of NHC-Fe complexes in organic catalysis are available, although significant work has been reported in the related field of biocatalysis. Contrastingly, the chemistry of NHC-Ru complexes has reached an unprecedented level of maturity, thanks to the relentless research efforts thrown into the development of olefin metathesis catalysts. Other carbon skeletal transformations based on NHC-Ru promoters include cyclopropanation, allylation, or cycloisomerisation reactions. Lastly, with only two reports to date concerning olefin metathesis and transfer hydrogenation, NHC-Os-based catalysis can hardly be considered anything else than a curiosity. [less ▲]

By focusing on recent developments on natural and non-natural azasugars (iminocyclitols), this review bolsters the case for the role of olefin metathesis reactions (RCM, CM) as key transformations in the ... [more ▼]

By focusing on recent developments on natural and non-natural azasugars (iminocyclitols), this review bolsters the case for the role of olefin metathesis reactions (RCM, CM) as key transformations in the multistep syntheses of pyrrolidine-, piperidine-and azepane-based iminocyclitols, as important therapeutic agents against a range of common diseases and as tools for studying metabolic disorders. Considerable improvements brought about by introduction of one or more metathesis steps are outlined, with emphasis on the exquisite steric control and atom-economical outcome of the overall process. The comparative performance of several established metathesis catalysts is also highlighted. [less ▲]

During the last decade or so, the emergence of the metathesis reaction in organic synthesis has revolutionised the strategies used for the construction of complex molecular structures. Olefin metathesis ... [more ▼]

During the last decade or so, the emergence of the metathesis reaction in organic synthesis has revolutionised the strategies used for the construction of complex molecular structures. Olefin metathesis is indeed particularly suited for the construction of small open-chain molecules and macrocycles using crossmetathesis and ring-closing metathesis, respectively. These reactions serve, inter alia, as key steps in the synthesis of various agrochemicals and pharmaceuticals such as macrocyclic peptides, cyclic sulfonamides, novel macrolides, or insect pheromones. The present chapter is aiming at illustrating the great synthetic potential of metathesis reactions. Shortcomings, such as the control of olefin geometry and the unpredictable effect of substituents on the reacting olefins, will also be addressed. Examples to be presented include epothilones, amphidinolides, spirofungin A, and archazolid. Synthetic approaches involving silicon-tethered ring-closing metathesis, relay ring-closing metathesis, sequential reactions, domino as well as tandem metathesis reactions will also be illustrated. [less ▲]